Thiazolylimidazole derivatives and their use as inhibitors of microsomal triglyceride transfer protein

ABSTRACT

The present invention relates to thiazolylimidazole derivatives of the general formula (I) in which: G represents a bond or a divalent radical chosen from the groups g1, g2 and g3; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y and Z are as defined in the description. Application of the compounds of the formula (I) to the treatment of hypertriglyceridaemia, hypercholesterolaemia and dyslipidaemia.

The invention relates to compounds that are inhibitors of microsomaltriglyceride transfer protein (MTP), to pharmaceutical compositionscomprising them, and to the use thereof in medicine.

MTP (microsomal triglyceride transfer protein) is a transfer proteinlocated in the reticulum of hepatocytes and enterocytes which catalysesthe assembly of biomolecules that transport triglycerides, the apo Blipoproteins.

The term apo B more particularly denotes apoprotein 48 of the intestineand apoprotein 100 of the liver.

Mutations in MTP or in the B apoproteins are reflected in man by verylow levels or even an absence of apo B lipoproteins. The lipoproteinscontaining apo B (chylomicrons, Very Low Density Lipoproteins) and theirmetabolic residues (chylomicron remnants, Low Density Lipoproteins) arerecognized as being a major risk factor in the development ofatherosclerosis, a major cause of death in industrialized countries.

It is observed that, in individuals who are heterozygous for thesemutations, levels reduced on average by a half are associated with a lowcardiovascular risk (C. J. Glueck, P. S. Gartside, M. J. Mellies, P. M.Steiner, Trans. Assoc. Am. Physicians, 90, 184 (1977)). This suggeststhat modulation of the secretions of triglyceride-rich lipoproteins bymeans of MTP antagonists and/or of secretion of apo B might be useful inthe treatment of atherosclerosis and more broadly of pathologiescharacterized by an increase in apo B lipoproteins.

Molecules that inhibit MTP and/or the secretion of apo B might thus beuseful for the treatment of diabetes-related hypertriglyceridaemia,hypercholesterolaemia and dyslipidaemia, and also for the prevention andtreatment of obesity.

Molecules of thiazolylpiperidine structure having an inhibitory activityon MTP and/or on apoB secretion form the subject of the as yetunpublished French patent application FR 03 07670.

It has now been discovered that other novel compounds with a structureof thiazolylimidazole type also have inhibitory properties on MTP and/oron apoB secretion. As a result of this activity, these novel compoundshave an entirely advantageous possible application in the treatment ofdiabetes-related hypertriglyceridaemia, des hypercholesterolaemia anddyslipidaemia, and also in the prevention and treatment of obesity.

Thus, the present invention relates firstly to the compounds ofthiazolylimidazole structure of the general formula (I):

in which:

-   -   G represents a bond or a divalent radical chosen from the groups        g1, g2 and g3 below:

-   -   R¹ is chosen from hydrogen and an alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl or        alkoxycarbonyl radical;    -   R² and R³, which may be identical or different, are chosen,        independently of each other, from a hydrogen atom, an alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl radical and a radical —NRR′;    -   R⁴, R⁵ and R⁶, which may be identical or different, are chosen,        independently of each other, from a hydrogen atom and an alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl radical;    -   R and R′, which may be identical or different, represent,        independently of each other, a hydrogen atom or a radical chosen        from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl        and heteroaryl; or together form, with the nitrogen atom that        bears them, a heterocycle, or together form the double bond of        an alken-1-yl radical;    -   Y represents an oxygen or sulfur atom; and    -   Z represents —NH— or an oxygen atom;

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and possible oxidized forms, especially amine    oxides, thereof, the solvates and the hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

The definitions that follow specify the natures of the various groupsand radicals defined above. Unless otherwise mentioned, thesedefinitions apply for all the terms of the present invention thusexplained.

The term “halogen atom” denotes a fluorine, chlorine, bromine or iodineatom.

The term “alkyl” denotes a linear or branched alkyl radical containingfrom 1 to 12 carbon atoms, optionally substituted by one or morechemical species, which may be identical or different, chosen from ahalogen atom, an oxo, thioxo, hydroxyl, thiol, —NRR′ (where R and R′,which may be identical or different, are as defined above), cyano, nitroor carboxyl group, and an alkoxy, alkenyloxy, alkynyloxy, alkylthio,alkyldisulfanyl (alkyl-S—S—), alkylsulfinyl (alkyl-S(═O)—),alkylsulfonyl (alkyl-S(═O)₂—), alkenylthio, alkynylthio, alkylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

Examples of alkyl radicals, which may be optionally substituted asindicated above, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,hexyl, isohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 1,3-dimethylbutyl, 1-ethylbutyl,1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl,4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl,5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and7,7-dimethyloctyl.

The term “alkenyl” denotes a linear or branched alkyl radical comprisingat least one unsaturation in double bond form and containing from 2 to12 carbon atoms, optionally substituted by one or more chemical species,which may be identical or different, chosen from a halogen atom, an oxo,thioxo, hydroxyl, thiol, —NRR′ (in which R and R′, which may beidentical or different, are as defined above), cyano, nitro or carboxylgroup, and an alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkyldisulfanyl(alkyl-S—S—), alkylsulfinyl (alkyl-S(═O)—), alkylsulfonyl(alkyl-S(═O)₂—), alkenylthio, alkynylthio, alkylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

Examples of alkenyl radicals, which may be optionally substituted asindicated above, are ethylenyl, propenyl, propadienyl, butenyl,butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl,heptadienyl, octenyl, octadienyl, nonenyl, nonadienyl, decenyl anddecadienyl, and also the branched isomers thereof, the absence ofindication of the position of the double bond(s) being necessarilyunderstood as meaning that no limitation is placed on the doublebond(s). For example, the “pentenyl” radical includes, withoutpreference, the pent-1-en-1-yl, pent-2-en-1-yl and pent-3-en-1-ylradicals, but also the pent-1-en-2-yl, pent-2-en-2-yl and pent-3-en-2-ylradicals, as well as the pent-1-en-3-yl, pent-2-en-3-yl andpent-3-en-3-yl radicals.

The term “alkynyl” denotes a linear or branched alkyl radical comprisingat least one unsaturation in triple bond form and containing from 2 to12 carbon atoms, optionally substituted by one or more chemical species,which may be identical or different, chosen from a halogen atom, an oxo,thioxo, hydroxyl, thiol, —NRR′ (in which R and R′, which may beidentical or different, are as defined above), cyano, nitro or carboxylgroup, and an alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkyldisulfanyl(alkyl-S—S—), alkylsulfinyl (alkyl-S(═O)—), alkylsulfonyl(alkyl-S(═O)₂—), alkenylthio, alkynylthio, alkylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

Examples of alkynyl radicals, which may be optionally substituted asindicated above, are ethynyl, propynyl, propadiynyl, butynyl,butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl, heptynyl,heptadiynyl, octynyl, octadiynyl, nonynyl, nonadiynyl, decynyl anddecadiynyl, and also the branched isomers thereof, the absence ofindication of the position of the double bond(s) being necessarilyunderstood as meaning that no limitation is placed on the doublebond(s). For example, the “pentynyl” radical includes, withoutpreference, the pent-1-yn-1-yl, pent-2-yn-1-yl and pent-3-yn-1-ylradicals, but also the pent-1-yn-2-yl, pent-2-yn-2-yl and pent-3-yn-2-ylradicals, as well as the pent-1-yn-3-yl, pent-2-yn-3-yl andpent-3-yn-3-yl radicals.

The term “cycloalkyl” denotes a monocyclic, bicyclic or tricyclic,bridged or unbridged cycloalkyl radical containing from 3 to 13 carbonatoms, optionally comprising one or more double bonds, also includingspirane compounds, and optionally substituted by one or more chemicalspecies, which may be identical or different, chosen from a halogenatom, an oxo, thioxo, hydroxyl, thiol, —NRR′ (in which R and R′, whichmay be identical or different, are as defined above), cyano, nitro orcarboxyl group, and an alkyl, especially substituted by one or morehalogen atoms, in particular perhaloalkyl, for instance trifluoromethyl,alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio,alkyldisulfanyl (alkyl-S—S—), alkylsulfinyl (alkyl-S(═O)—),alkylsulfonyl (alkyl-S(═O)₂—), alkenylthio, alkynylthio, alkylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

Examples of cycloalkyl groups, which are optionally substituted asindicated above, are especially cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, adamantyl,diamantyl, norbornyl and bornyl groups.

The term “heterocycloalkyl” denotes a monocyclic, bicyclic or tricyclicradical containing a total of from 3 to 13 atoms, among which 1, 2, 3 or4 are chosen, independently of each other, from nitrogen, oxygen andsulfur, the other atoms being carbon atoms, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds, alsoincluding spirane compounds, and being optionally substituted by one ormore chemical species, which may be identical or different, chosen froma halogen atom, an oxo, thioxo, hydroxyl, thiol, —NRR′ (in which R andR′, which may be identical or different, are as defined above), cyano,nitro or carboxyl group, and an alkyl, especially substituted by one ormore halogen atoms, in particular perhaloalkyl, for instancetrifluoromethyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy,alkylthio, alkyldisulfanyl (alkyl-S—S—), alkylsulfinyl (alkyl-S(═O)—),alkylsulfonyl (alkyl-S(═O)₂—), alkenylthio, alkynylthio, alkylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

In particular, saturated or partially unsaturated, monocyclicheterocycles of 5 to 8 atoms are saturated, or partially unsaturated,derivatives of the heteroaryls defined later. More particularly, amongthe heterocycloalkyl radicals that may be mentioned are morpholino,morpholinyl, piperidyl, thiazolidinyl, oxazolidinyl, tetrahydrothienyl,tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, isoxazolidinyl,imidazolidinyl and pyrazolidinyl radicals.

The term “aryl” denotes a monocyclic, bicyclic or tricyclic aryl radicalcontaining from 6 to 14 carbon atoms, optionally substituted by one ormore chemical species, which may be identical or different, chosen froma halogen atom, a hydroxyl, thiol, —NRR′ (in which R and R′, which maybe identical or different, are as defined above), cyano, nitro orcarboxyl group, and an alkyl, especially substituted by one or morehalogen atoms, in particular perhaloalkyl, for instance trifluoromethyl,alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio,alkyldisulfanyl (alkyl-S—S—), alkylsulfinyl (alkyl-S(═O)—),alkylsulfonyl (alkyl-S(═O)₂—), alkenylthio, alkynylthio, a phosphoricacid derivative [(alkyl-0)₂—P—O-alkyl], alkylcarbonyl, alkoxycarbonyl,alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

Aryl radicals that may be mentioned, in a non-limiting manner, includephenyl, naphthyl, anthryl and phenanthryl radicals.

The term “heteroaryl” denotes a monocyclic, bicyclic or tricyclicaromatic radical containing a total of from 3 to 13 atoms, among which1, 2, 3 or 4 are chosen, independently of each other, from nitrogen,oxygen and sulfur, optionally in oxidized form (in the case of nitrogenand sulfur), the other atoms being carbon atoms, the said heteroarylradical being optionally substituted by one or more chemical species,which may be identical or different, chosen from a halogen atom, ahydroxyl, thiol, —NRR′ (in which R and R′, which may be identical ordifferent, are as defined above), cyano, nitro or carboxyl group, and analkyl, especially substituted by one or more halogen atoms, inparticular perhaloalkyl, for instance trifluoromethyl, alkenyl, alkynyl,alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkyldisulfanyl (alkyl-S—S—),alkylsulfinyl (alkyl-S(═O)—), alkylsulfonyl (alkyl-S(═O)₂—),alkenylthio, alkynylthio, alkylcarbonyl, alkoxycarbonyl,alkylcarbonylamino, alkoxycarbonylamino, arylcarbonyl,arylcarbonylamino, (di)alkylaminocarbonyl, cycloalkyl, cycloalkoxy,cycloalkylthio, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylthio, aryl, aryloxy, arylthio, heteroaryl,heteroarylcarbonyl, heteroaryloxy or heteroarylthio radical.

Preferably, at least one of the monocycles constituting the heterocyclecontains from 1 to 4 endocyclic hetero atoms and more preferably from 1to 4 endocyclic hetero atoms. According to the invention, theheterocyclic polycyclic nucleus consists of one or more monocycles eachcontaining from 5 to 8 atoms included in the ring.

Examples of heteroaryl radicals, optionally substituted as has just beendescribed, are radicals derived from heteroaromatic compounds, such aspyridine, furan, thiophene, pyrrole, imidazole, thiazole, isothiazole,isoxazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines,oxazole, pyrazole, oxadiazole, triazole and thiadiazole. Among thepreferred heteroaryls that may be mentioned are pyridyls, pyrimidinyls,triazolyls, thiadiazolyls, oxazolyls, thiazolyls and thienyls.

Examples of bicyclic heteroaryl radicals in which each monocyclecontains from 5 to 8 endocyclic atoms are derived from aromaticcompounds chosen from indolizine, indole, isoindole, benzofuran,benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane,benzothiofurazane, purine, quinoline, isoquinoline, cinnoline,phthalazine, quinazoline, quinoxaline, naphthyridines,pyrazolotriazines, pyrazolopyrimidine and pteridine.

Among the heteroaryls defined above, quinolyl, pyridyl, benzotriazolyl,triazolyl, acridyl, phenazinyl and carbazolyl radicals are preferred.

For the compounds of the formula (I) presented above, the term“geometrical isomer” means a cis/trans or E/Z isomerism. Moreparticularly, the possible double bond(s) present in the varioussubstituents of the compounds of the general formula (I) may be of E orZ configuration. These pure or impure geometrical isomers, alone or as amixture, form an integral part of the compounds of the formula (I).

The term “optical isomer” includes all the isomeric forms, alone or asmixtures, resulting from the presence of one or more axes and/or centresof symmetry in the molecule, and resulting in rotation of a beam ofpolarized light. The term “optical isomer” more particularly includesenantiomers and disasteroisomers, in pure form or as a mixture.

The acids capable of forming pharmaceutically acceptable salts with thecompounds of the formula (I) above are organic or mineral acids.Non-limiting examples that may be mentioned include hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, tartaric acid, citricacid, maleic acid, acetic acid, fumaric acid, alkanesulfonic acid,naphthalenesulfonic acid, para-toluenesulfonic acid, bistrifluoroaceticacid and camphoric acid.

The bases capable of forming pharmaceutically acceptable salts with thecompounds of the formula (I) above are mineral or organic bases. Amongthese bases, non-limiting examples that may be mentioned include sodiumhydroxide, potassium hydroxide, ammonia, diethylamine, triethylamine,ethanolamine, diethanolamine, piperidine, piperazine, morpholine, basicamino acids, such as arginine and lysine, osamines, for examplemeglumine, and amino alcohols, such as 3-aminobutanol and2-aminobutanol.

The invention especially covers the pharmaceutically acceptable salts,as indicated above, but also salts allowing a suitable separation orcrystallization of the compounds of the formula (I), such as the saltsobtained with chiral amines,

The compounds of the formula (I) above also comprise the prodrugs ofthese compounds.

The term “prodrugs” means compounds which, once administered to thepatient, are chemically and/or biologically converted by the livingbody, into compounds of the formula (I).

Among the compounds of the formula (I) according to the invention thatare preferred are those for which the radical R² represents hydrogen,the other substituents being as defined above,

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

Preference is also given to the compounds of the formula (I) accordingto the invention for which the radical R³ represents hydrogen, the othersubstituents being as defined above,

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

Another preferred group of compounds according to the present inventionconsists of compounds of the general formula (I) in which the radicalsR⁴ and R⁵, independently of each other, represent an alkyl radical, theother substituents being as defined above,

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

Another preferred group of compounds according to the present inventionconsists of compounds of the general formula (I) in which the radical R⁶represents an aryl or heteroaryl radical, the other substituents beingas defined above,

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

Another preferred group of compounds according to the present inventionconsists of compounds of the formula (I) in which the thiazolyl radicalis branched in position 3 or in position 4 of the piperidine nucleus,preferably in position 4 of the piperidine nucleus.

Another preferred group of compounds according to the present inventionconsists of compounds of the general formula (I) in which G representsthe radical g1, preferably in which Y represents an oxygen atom, theother substituents being as defined above,

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

Another preferred group of compounds according to the present inventionconsists is of compounds of the general formula (I) in which theradicals R² and R³ each represent a hydrogen atom, the radicals R⁴ andR⁵ represent, independently of each other, an alkyl radical, the radicalR⁶ represents an aryl or heteroaryl radical, the thiazolyl radical isbranched in position 4 of the piperidine nucleus, and G represents theradical g1 in which Y represents an oxygen atom, the other substituentsbeing as defined above,

-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

Another preferred group of compounds of the invention consists ofcompounds of the general formula (I) in which R¹ represents an arylradical, especially phenyl, substituted by one or more aryl and/or alkylradicals.

The compounds of the general formula (I) in which R¹ represents abiphenyl radical, optionally substituted by one or more alkyl radicals,preferably methyl, ethyl or propyl, and/or with a perhaloalkyl orperhaloalkoxy radical, are most particularly preferred. The compounds ofthe general formula (I) in which R¹ represents a substituted biphenylradical, for example a trifluoromethylbiphenyl ormethyltrifluoromethoxybiphenyl radical, are more particular preferred.

A preferred subgroup of compounds consists of compounds of the generalformula (I) in which G represents the radical g1, with Y representing anoxygen atom, R¹ represents a biphenyl radical, optionally substituted byone or more alkyl radicals, preferably methyl, ethyl or propyl, and/or atrifluoromethyl or trifluoromethoxy radical,

-   the other substituents being as defined above,-   the possible geometrical and/or optical isomers, epimers and various    tautomeric forms, and optional oxidized forms, especially amine    oxides, thereof, and the solvates and hydrates of these compounds;    and also the possible pharmaceutically acceptable salts thereof with    an acid or a base, or the pharmaceutically acceptable prodrugs of    these compounds.

It should be understood that the preferences for the substituentsindicated in the various subgroups defined above can be combined to formother subgroups of preferred compounds of the formula (I) according tothe present invention.

Particularly preferred examples of compounds according to the presentinvention are chosen from:

-   -   {4-[4-(1,5-dimethyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;    -   {4-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;    -   {3-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;    -   {4-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone;    -   {4-[4-(1-ethyl-5-methyl-4-(pyrid-3-yl)-1H-imidazol-2-yl)thiazol-2-yl]-piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;    -   {4-[4-(1-ethyl-5-methyl-4-(pyrid-2-yl)-1H-imidazol-2-yl)thiazol-2-yl]-piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;        and    -   {4-[4-(1-ethyl-5-methyl-4-(pyrid-2-yl)-1H-imidazol-2-yl)thiazol-2-yl]-piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone;    -   the optical isomers thereof, oxidized forms, solvates and        hydrates of these compounds;        and also the possible pharmaceutically acceptable salts thereof        with an acid, or the pharmaceutically acceptable prodrugs of        these compounds.

The compounds of the present invention can be prepared from thecompounds of the formula (II):

-   -   in which T represents a labile protecting group, for example        tert-butoxycarbonyl (BOC), and R² is as defined above,    -   which is reacted with ethyl R³-bromopyruvate (in which R³ is as        defined above), generally in equimolar proportions, in a polar        solvent, for example dimethylformamide, in the presence of an        excess of base, preferably an organic base, such as        triethylamine, at a suitable temperature, for example at room        temperature, for a period ranging from 1 to 40 hours and        preferably between 4 and 18 hours,    -   so as to form the thiazolyl ring and give the compound of the        formula (III):

in which T, R² and R³ are as defined above,

-   -   which compound of the formula (III) is then saponified with a        base, of alkali metal or alkaline-earth metal hydroxide type,        for example sodium hydroxide, in polar medium, for instance        tetrahydrofuran and/or water, especially a 2:1        tetrahydrofuran/water mixture, at room temperature, for a period        ranging from 1 to 12 hours, so as to form the salt of the        formula (IV):

in which T, R² and R³ are as defined above, and M⁺ represents the alkalimetal or alkaline-earth metal cation derived from the base that isuseful for the saponification reaction,

-   -   which compound of the formula (IV) is next hydrolysed to a        compound of the formula (V):

in which R², R³ and T are as defined above,

-   -   which compound of the formula (V) is then converted to a        corresponding amide of the formula (VI):

-   -   in which R², R³, R⁴, R⁵, R⁶ and T are as defined above,    -   via the action of an amine of the formula (VIa):

-   -   in which R⁴, R⁵ and R⁶ are as defined above,    -   generally in equimolar proportions, in the presence of a base,        preferably an organic base, such as diisopropylethylamine        (DIPEA), and a catalyst, for example        O-benzotriazol-1-yl-N,N,N′,N′-tetraethyluronium        hexafluorophosphate (HBTU), in a polar aprotic solvent, such as        dimethylformamide, at room temperature, for a period possibly        ranging from 1 to 50 hours and generally from 4 to 20 hours,    -   the compound of the formula (VI) then being used in a reaction        for deprotection of the amine function of the piperidine ring,        via the action of an organic or mineral acid, for example        hydrochloric acid or trifluoroacetic acid, in dichloromethane        (DCM) or dioxane medium, at room temperature, for a period        ranging from a few minutes to several hours, generally ranging        from 5 minutes to 12 hours, to give the compound of the formula        (VII):

-   -   in which R², R³, R⁴, R⁵ and R⁶ are as defined above,    -   which compound of the formula (VII) is then subjected to the        action of a compound chosen from:

-   -   in which X represents a halogen atom, preferably chlorine, R¹, Y        and Z being as defined above,    -   in the presence of a base, preferably an organic base, such as        diisopropylethylamine (DIPEA), and a catalyst, for example        O-benzotriazol-1-yl-N,N,N′, N′-tetraethyluronium        hexafluorophosphate (HBTU), in a polar aprotic solvent, such as        dimethylformamide, at room temperature, for a period possibly        ranging from 1 to 50 hours and generally from 4 to 20 hours,    -   to give the compound of the formula (VIII):

-   -   in which G, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above,    -   which is finally subjected to a cyclization reaction (formation        of the imidazole ring), in the presence of a cyclizing agent,        such as ammonium trifluoroacetate, also acting as solvent, at a        suitable temperature, for example in the region of 150° C., for        a period generally of between 5 and 15 minutes,    -   to give the compound of the formula (I) as defined above.

According to one variant, the compounds of the formula (I) can also beprepared by reacting a compound of the formula chosen from:

-   -   in which R1, Y and Z are as defined above,    -   with a compound of the formula (IX):

-   -   in which R² is as defined above,    -   in the presence of an acyl chloride, such as oxalyl chloride, in        basic medium, for example triethylamine, and in an apolar        aprotic solvent, for example dichloromethane, at room        temperature, for a period ranging from 1 to 50 hours and        generally from 4 to 20 hours,    -   to give the compound of the formula (X):

in which G, R¹ and R² are as defined above,

-   -   which is then converted into the corresponding thioamide of the        formula (XI) via the action of Lawesson's reagent, in a polar        solvent, for example dimethyl ether, at a temperature of about        50° C., for a period generally of about 2.5 hours:

in which G, R¹ and R² are as defined above,

-   -   the thiazole ring then being formed in a manner similar to that        presented above for the formation of the compound of the formula        (III), via the action of ethyl R³-bromopyruvate (in which R³ is        as defined above), to give the compound of the formula (XII):

in which G, R¹, R² and R³ are as defined above,

-   -   which compound of the formula (XII) is then saponified, in a        manner similar to that for the formation of the compound of the        formula (IV), to give the acid of the formula (XIII):

in which G, R¹, R² and R³ are as defined above,

-   -   which compound of the formula (XIII) is then subjected to the        action of an amine of the formula (VIa) as defined above, in        order to give the compounds of the formula (VIII) defined above,        which are finally cyclized, as indicated above, to give the        compounds of the formula (I).

In the processes described above, it should be understood that theoperating conditions may vary substantially as a function of thedifferent substituents G, R¹, R², R³, R⁴, R⁵ and R⁶ present in thecompounds of the formula (I) that it is desired to prepare. Suchvariations and adaptations are readily accessible to a person skilled inthe art, for example from scientific reviews, the patent literature,Chemical Abstracts, and computer databases, including the Internet.

The amine of the formula (VIa):

-   -   in which R⁴, R⁵ and R⁶ are as defined for the compounds of the        formula (I),    -   can advantageously be prepared according to one of the synthetic        routes presented in the following scheme, and in which the        various substituents are as defined in the present invention:

The present invention also relates to pharmaceutical compositionscomprising an effective pharmaceutical amount of at least one compoundof the formula (I), as defined above, in combination with one or morepharmaceutically acceptable excipients and/or vehicles.

These compositions can be administered orally in the form ofimmediate-release or controlled-release tablets, gel capsules orgranules, intravenously in the form of an injectable solution,transdermally in the form of an adhesive transdermal device, or locallyin the form of a solution, cream or gel.

A solid composition for oral administration is prepared by adding to theactive principle a filler and, where appropriate, a binder, adisintegrant, a lubricant, a colorant or a flavour enhancer, and byforming the mixture into a tablet, a coated tablet, a granule, a powderor a capsule.

Examples of fillers include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide, and examples ofbinders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose,methylcellulose, acacia, gum tragacanth, gelatine, Shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin.

Examples of lubricants include magnesium stearate, talc, polyethyleneglycol, silica and hardened plant oils. The colorant may be any colorantpermitted for use in medicaments.

Examples of flavour enhancers include cocoa powder, mint in herb form,aromatic powder, mint in oil form, borneol and cinnamon powder. Itshould be understood that the tablet or granule may be suitably coatedwith sugar, gelatine or the like.

An injectable form comprising the compound of the present invention asactive principle is prepared, where appropriate, by mixing the saidcompound with a pH regulator, a buffer agent, a suspension agent, asolubilizer, a stabilizer, a tonicity agent and/or a preserving agent,and by converting the mixture into a form for intravenous, subcutaneousor intramuscular injection, according to a conventional process. Whereappropriate, the injectable form obtained may be lyophilized via aconventional process.

Examples of suspension agents include methylcellulose, polysorbate 80,hydroxyethylcellulose, acacia, powdered gum tragacanth, sodiumcarboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilizers include castor oil solidified withpolyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitanmonolaurate and the ethyl ester of castor oil fatty acid.

In addition, the stabilizer includes sodium sulfite, sodium metasulfiteand ether, while the preserving agent includes methylpara-hydroxybenzoate, ethyl para-hydroxybenzoate, sorbic acid, phenol,cresol and chlorocresol.

The compounds of the formula (I) and the pharmaceutical compositionsaccording to the present invention are useful as microsomal triglyceridetransfer protein (MTP) inhibitors.

Thus, the present invention also relates to the use of a compound of theformula (I) or a pharmaceutical composition as defined above, for thepreparation of a medicament that is a microsomal triglyceride transferprotein inhibitor.

More specifically, a subject of the present invention is the use of acompound of the formula (I) or of a pharmaceutical composition asdefined above for the preparation of a medicament for the preventionand/or treatment of diabetes-related hypercholesterolaemia,hypertriglyceridaemia, hyperlipidaemia, pancreatitis, hyperglycaemia,obesity, atherosclerosis and dyslipidaemia.

The compounds according to the present invention also have an inhibitoryactivity on the secretion of the B apoproteins (apo B). In this respect,a subject of the present invention is also the use of a compound of theformula (I) or of a pharmaceutical composition as defined above, for thepreparation of a medicament for inhibiting the secretion of the Bapoproteins (apo B).

The examples that follow illustrate the present invention withoutlimiting it in any way.

EXAMPLES OF THIAZOLYLIMIDAZOLE COMPOUNDS ACCORDING TO THE INVENTIONExample 1{4-[4-(1-Ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone

Step a)

tert-Butyl 4-(4-ethoxycarbonylthiazol-2-yl)piperidine-1-carboxylate

tert-Butyl 4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate(Maybridge) (85 mmol; 20.8 g) is dissolved in 250 ml ofdimethylformamide and placed at 5° C. Ethyl bromopyruvate (1 eq.; 85mmol; 16.6 g) dissolved in 50 ml of dimethylformamide is added dropwise.The reaction medium is stirred overnight and excess triethylamine isthen added dropwise.

The reaction medium is evaporated and the residual brown oil is taken upin ethyl acetate and washed with water (twice) and then with saturatedsodium chloride solution (twice). The organic phase is dried over sodiumsulfate and evaporated to dryness. The crude product is chromatographedon silica, eluting with dichloromethane to dichloromethane/3% methanol,to give 20.5 g of the expected product in the form of oily crystals.TLC: 1/1 ethyl acetate/hexane: Rf=0.55

Yield=71%.

Step b)

tert-Butyl 4-(4-carboxythiazol-2-yl)piperidine-1-carboxylate

tert-Butyl 4-(4-ethoxycarbonylthiazol-2-yl)piperidine-1-carboxylate (60mmol; 20.4 g) is dissolved in 225 ml of a mixture of tetrahydrofuran andwater (2/1), and 1N sodium hydroxide (2 eq.; 120 mmol; 120 ml) is addeddropwise.

The reaction medium is stirred at room temperature overnight.

The reaction medium is washed with ether and the aqueous phase is thenacidified with saturated nitric acid solution. The precipitate isfiltered off, washed with water and dried to give 15.5 g ofcream-coloured crystals.

TLC: 1/1/1 CH₂Cl₂/EtOAc/MeOH: Rf=0.6.

Yield: 83%.

Step c)

tert-Butyl4-{4-[ethyl(1-methyl-2-oxo-2-phenylethyl)carbamoyl]thiazol-2-yl}-piperidine-1-carboxylate

tert-Butyl 4-(4-carboxythiazol-2-yl)piperidine-1-carboxylate (6.5 mmol;2.03 g) is dissolved in 40 ml of anhydrous dimethylformamide and placedunder an inert atmosphere, and 2-(ethylamino)propiophenone hydrochloride(1 eq.; 6.5 mmol; 1.39 g), HBTU (1 eq.; 6.5 mmol; 2.47 g) andN-ethyldiisopropylamine (3.5 eq.; 22.75 mmol; 3.97 ml) are then added.

The reaction medium is stirred at room temperature overnight.

The reaction medium is evaporated to dryness and then taken up indichloromethane and washed with saturated potassium carbonate (K₂CO₃)solution, citric acid solution and water (twice). The organic phase isdried over sodium sulfate and then evaporated to dryness. The crudeproduct is chromatographed on silica, using a 1/1 ethyl acetate/hexanemixture as eluent (Rf=0.55) to give 2.6 g of expected product in theform of an oil.

Yield: 85%.

Step d)

4-{4-[Ethyl(1-methyl-2-oxo-2-phenylethyl)carbamoyl]thiazol-2-yl}piperidiniumchloride

tert-Butyl4-{4-[ethyl(1-methyl-2-oxo-2-phenylethyl)carbamoyl]thiazol-2-yl}-piperidine-1-carboxylate(5.5 mmol; 2.59 g) is dissolved in 13.75 ml of a 4M solution ofhydrochloric acid in dioxane.

The reaction medium is stirred at room temperature overnight and is thenevaporated to dryness to give 2.24 g of a white solid.

Yield=quantitative.

Step e)

2-[1-(6-Methyl-4′-trifluoromethoxybiphenyl-2-carbonyl)piperid-4-yl]thiazole-4-carbonyl[1N-ethyl-N-(1-methyl-2-oxo-2-phenylethyl)]amide

The title compound was obtained according to a procedure similar to thatused for the preparation of tert-butyl4-{4-[ethyl(1-methyl-2-oxo-2-phenylethyl)carbamoyl]thiazol-2-yl}piperidine-1-carboxylate.

TLC: 1/1 CH₂Cl₂/EtOAc: Rf=0.47 LC-MS: (ES+) 650.4 (M+H) Yield: 88%.

Step f

{4-[4-(1-Ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone

2-[1-(6-Methyl-4′-trifluoromethoxybiphenyl-2-carbonyl)piperid-4-yl]thiazole-4-carbonyl[N-ethyl-N-(1-methyl-2-oxo-2-phenylethyl)]amide(0.195 g; 0.3 mmol) is mixed with ammonium trifluoroacetate (10 eq.; 3.0mmol; 393 mg) under a nitrogen atmosphere. The mixture is heated for 5minutes at 150° C. with stirring, the heating is removed and water isadded.

The reaction medium is then extracted twice with ethyl acetate, and theorganic phases are then combined and washed with water, dried oversodium sulfate and then evaporated to dryness to give 0.171 g of a purewhite solid, corresponding to the expected product.

TLC: 1:1 CH₂Cl₂/EtOAc; Rf=0.48 MS: ES+ 632.6 Yield: 90%

Examples 2 to 7

The compounds of Examples 2 to 7, presented in Table I below, wereprepared in a similar manner.

TABLE 1 Compound R¹ G R² R³ R⁴ R⁵ R⁶ 2

—H —H —CH₃ —CH₃ —C₆H₅ 3

—H —H —C₂H₅ —CH₃ —C₆H₅ 4

—H —H —C₂H₅ —CH₃

5

—H —H —C₂H₅ —CH₃

6

—H —H —C₂H₅ —CH₃

7*

—H —H —C₂H₅ —CH₃ —C₆H₅ *In the compound of Example 7, the thiazolenucleus is branched in position 3 of the piperidine ring. For all theother examples (1 to 6), the thiazole nucleus is branched in position 4of the piperidine ring.

The results of the spectral analyses (NMR or mass) of the compounds ofExamples 1 to 7 are as follows:

Compound ¹H NMR Mass 1 ES+ 632.6 2 δ ppm (CDCl₃): 1.41-3.53 (14H, m);4.48-4.87 (1H, m); 6.80-8.25 (14H, m). 3 δ ppm (CDCl₃): 1.23-2.14 (m,7H); 2.23-3.46 (m, 4H); 2.37-2.47 (m, 3H); 4.25-4.81 (m, 3H); 7.25-7.78(m, 14H). 4 ES+ 602.4 5 ES+ 602.5 6 ES+ 632.6 7 δ ppm (DMSO-d6):0.78-4.77 (17H, m); 7.07-8.08 (14H, m).

BIOLOGICAL EXPERIMENTAL SECTION Biological Activity Tests

Analysis of the Inhibition of MTP Activity

The inhibition of the activity of microsomal triglyceride transferprotein (MTP) was tested by using the following operating protocol.

The inhibition of MTP activity with a compound can be quantified byobserving the inhibition of the transfer of a labelled triglyceride,from a donor particle to an acceptor particle, in the presence of MTP.The procedure for the preparation of MTP is based on the method byWetterau and Zilversmit (Biochem. Biophys. Acta (1986) 875, 610). A fewgrams of golden hamster liver are taken and then rinsed several times ina 250 mM sucrose solution at 0° C. All the following steps proceed at+4° C. A homogenate at a concentration of 50% in 250 mM sucrose isprepared using a Teflon mill and then centrifuged for 10 minutes at 10000×g at +4° C. The supernatant is then centrifuged at 105 000×g for 75minutes at +4° C. The supernatant is discarded and the microsomal pelletis taken up in 3 ml (per g of starting liver) of Tris/HCl 150 mM pH 8.0.1 ml aliquot fractions are stored at −80° C. until the time of use.

After thawing a fraction of microsomes (1 ml), 12 ml of refrigeratedTris/HCl 50 mM, KCl 50 mM, MgCl₂ 5 mM pH 7.4 buffers and 1.2 ml ofdeoxycholate (0.54% in water) are added. After incubation for 30 minutesat +4° C. with gentle agitation, the suspension is centrifuged at 105000×g for 75 minutes. The supernatant comprising the soluble MTP isdialysed against Tris/HCl 150 mM, NaCl 40 mM, EDTA 1 mM, 0.02% sodiumazide pH 7.4 buffer (5 times one litre over 2-3 days). The MTP is storedat +4° C., is stable for at least 30 days and is used in unmodified formin the test.

The donor particles (liposomes) are prepared from 208 μl ofL-phosphatidylcholine at a concentration of 10 mg/ml in chloroform, and480 μl of [3H]-triolein at a concentration of 0.5 mCi/ml in toluene.After stirring, the solution is evaporated under nitrogen, taken up in 6ml of Tris/HCl 50 mM, KCl 50 mM, MgCl₂ 5 mM pH 7.4 buffer and incubatedin an ultrasound bath for 30 minutes at room temperature. The liposomesare stored at +4° C. and sonicated again for 10 minutes before each use.

The acceptor particles are biotinylated low density lipoproteins(LDL-biot). These particles are supplied by the company Amersham.

The reaction mixture is prepared in untreated ½ well white plates(Corning Costar) by addition, in the following order, of: 5 μl of HEPES50 mM, NaCl-150 mM, BSA 0.1% (w/v), 0.05% sodium azide (w/v), pH 7.4buffer; 5 μl of liposomes; 5 μl of LDL-biot; 5 μl of test products inDMSO; 5 μl of MTP. After incubation for 18-24 hours at 37° C., thereaction is stopped by adding 100 μl of Amersham SPA (scintillationproximity assay) beads coupled to streptavidin, and the radioactivity iscounted using a Top Count (Packard) machine at least one hour later. Theinhibition of the transfer of the triglycerides with a compound isreflected by a reduction in the transferred radioactivity. Thepercentage inhibition for a given compound is determined relative tocontrols that do not comprise compounds in the reaction mixture.

The results are expressed in terms of the IC₅₀, i.e. the concentrationthat allows a 50% inhibition of MTP. These results are summarized inTable A below for a number of representative compounds of the invention.

TABLE A Example IC₅₀ (nM) 1 320.00 2 300.00 3 270.00 4 816.00 5 2542.006 1830.00

Analysis of the Secretion of Apo B in the HepG2 Human Cell Line:

The activity of a compound according to the invention can be evaluatedby measuring the inhibition of apo B secretion in HepG2 cells.

The HepG2 cells (ECACC-No. 85011430) are used as model in the study ofthe in vitro hepatic secretion of lipoproteins (Dixon J. and GinsbergH., J. Lipid. Res., 1993, 34, 167-179).

The HepG2 cells are cultured in Dulbecco's modified Eagle's mediumcomprising 10% foetal calf serum (DMEM and FBS-Gibco) in 96-well platesunder an atmosphere of 5% carbon dioxide for 24 hours (about 70%confluence).

The test compounds are dissolved at a concentration of 2 or 10 mM indimethyl sulfoxide (DMSO). Serial dilutions (1:3.16) are made in DMSOand are:added (1:200—Robot Multimek Beckman) to the growth medium (200μl) and then finally incubated for 24 hours in the various wellscontaining the HepG2 cells.

The 24-hour culture supernatant diluted to 1:5 (phosphate-bufferedsaline: PBS comprising 1% bovine serum albumin) is tested according to asandwich-ELISA method specific for human apo B.

The results are expressed in terms of IC₅₀, i.e. the concentration thatproduces a 50% inhibition of apo B secretion in the HepG2 cells.

These results are collated in Table B below for a number ofrepresentative compounds of the invention.

TABLE B Example IC₅₀ (nM) 1 369.00 2 616.00 3 390.00 4 1573.00 5 2624.006 2297.00 7 2088.00

1.{4-[4-(1,5-dimethyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;-{4-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;-{3-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;-{4-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone;-{4-[4-(1-ethyl-5-methyl-4-(pyrid-3-yl)-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;-{4-[4-(1-ethyl-5-methyl-4-(pyrid-2-yl)-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;-{4-[4-(1-ethyl-5-methyl-4-(pyrid-2-yl)-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone;or an optical isomer, epimer, tautomer, amine oxide, hydrate,pharmaceutically acceptable salt with an acid or a base.
 2. Apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of claim 1, in combination with one or morepharmaceutically acceptable vehicles.
 3. A method for the treatment ofdiabetes-related hypertriglyceridaemia, hypercholesterolaemia,dyslipidaemia, or for treatment of obesity, comprising administering toa host in need thereof an effective amount of a compound of claim 1.